Search Results (19)

Indomethacin, ibuprofen, and acetylsalicylic acid (ASA) are non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin (PG) synthesis. Previous studies in airway smooth muscle demonstrated that chronic exposure to testosterone (TES, 40 nM) enhances the relaxation induced by salbutamol and theophylline due to K⁺ channel increment, without modifying cyclooxygenase expression. This study examines how indomethacin, ibuprofen, and ASA affect K⁺ currents and the relaxation response to these bronchodilators. In organ baths, tracheas from young male guinea pigs chronically (48 h) treated with 40 nM TES showed increased relaxation to salbutamol and theophylline, which was completely abolished by indomethacin. Patch-clamp recordings revealed that TES increased salbutamol- and theophylline-induced K⁺ currents, and only indomethacin fully inhibited this potentiation; ibuprofen and ASA had partial effects. The involved currents included voltage-dependent K⁺ (K_V) and high-conductance Ca²⁺-activated K⁺ (BK_Ca) channels. Our results demonstrate that indomethacin exerts a dual action, inhibiting K⁺ channel activity and PG synthesis, unlike ibuprofen and ASA. This dual mechanism explains its stronger inhibitory effect on TES-enhanced ASM relaxation. These findings suggest that indomethacin may counteract the protective effects of TES, which promotes anti-inflammatory and smooth muscle-relaxing states. Therefore, it is advisable to exercise caution when prescribing indomethacin to young males with asthma, as the protective role of TES may diminish, potentially resulting in an exacerbation of asthma symptoms. Full article

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article

During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However, this process is often compromised in conditions like maternal high blood pressure, particularly in preeclampsia (PE), leading to fetal growth impairment. Currently, there is no cure for PE, partly due to the adverse effects of anti-hypertensive drugs on maternal and fetal health. This study aimed to investigate the vasodilator effect of extra virgin olive oil (EVOO) phenols on the reproductive vasculature, potentially benefiting both mother and fetus. Isolated uterine arteries (UAs) from pregnant rats were tested with EVOO phenols in a pressurized myograph. To elucidate the underlying mechanisms, additional experiments were conducted with specific inhibitors: L-NAME/L-NNA (10⁻⁴ M) for nitric oxide synthases, ODQ (10⁻⁵ M) for guanylate cyclase, Verapamil (10⁻⁵ M) for the L-type calcium channel, Ryanodine (10⁻⁵ M) + 2-APB (3 × 10⁻⁵ M) for ryanodine and the inositol triphosphate receptors, respectively, and Paxilline (10⁻⁵ M) for the large-conductance calcium-activated potassium channel. The results indicated that EVOO-phenols activate Ca²⁺ signaling pathways, generating nitric oxide, inducing vasodilation via cGMP and BKCa²⁺ signals in smooth muscle cells. This study suggests the potential use of EVOO phenols to prevent utero-placental blood flow restriction, offering a promising avenue for managing PE. Full article

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca²⁺-activated K⁺ (BK_Ca or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BK_Ca channels, responsible for the generation of the overall magnitude of Ca²⁺-activated K⁺ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca²⁺ ion concentrations collectively contribute to the activation of BK_Ca channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BK_Ca channels’ conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BK_Ca channels might influence cardiac electrical activity as well. Taken together, the BK_Ca channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo. Full article

Mechanisms by which BK_Ca (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BK_Ca channel activity, protein expression, and interaction with IP3R (inositol 1,4,5-trisphosphate receptor) were examined using patch clamp, Western blot analysis, and coimmunoprecipitation. On inside-out patches of VSMCs, the Ca²⁺-sensitivity and voltage-dependence of BK_Ca channels were similar between hypertensive and normotensive rats. In whole-cell patch clamp configuration, treatment of cells with the IP3R agonist, Adenophostin A (AdA), significantly increased BK_Ca channel currents in VSMCs of both strains of rats, suggesting IP3R-BK_Ca coupling; however, the AdA-induced increases in BK_Ca currents were attenuated in VSMCs of hypertensive rats, indicating possible IP3R-BK_Ca decoupling, causing BK_Ca dysfunction. Co-immunoprecipitation and Western blot analysis demonstrated that BK_Ca and IP3R proteins were associated together in VSMCs; however, the association of BK_Ca and IP3R proteins was dramatically reduced in VSMCs of hypertensive rats. Genetic disruption of IP3R-BK_Ca coupling using junctophilin-2 shRNA dramatically augmented Ang II-induced proliferation in VSMCs of normotensive rats. Subcutaneous infusion of NS1619, a BK_Ca opener, to reverse BK_Ca dysfunction caused by IP3R-BK_Ca decoupling significantly attenuated vascular hypertrophy in hypertensive rats. In summary, the data from this study demonstrate that loss of IP3R-BK_Ca coupling in VSMCs induces BK_Ca channel dysfunction, enhances VSMC proliferation, and thus, may contribute to vascular hypertrophy in hypertension. Full article

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH₃ lactotrophs. RFM increased the amplitude of Ca²⁺-activated K⁺ currents (I_K(Ca)) in pituitary GH₃ lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca²⁺-activated K⁺ channels (BK_Ca channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BK_Ca channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na⁺ current (I_Na) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of K_Ca1.1 channels with amino acid residues, thereby functionally affecting BK_Ca channels’ activity. This study is the first to present evidence that, in addition to inhibiting the I_Na, RFM effectively modifies the I_K(Ca), which suggests that it has an impact on neuronal function and excitability. Full article

H₂S is a gaseous signaling molecule enzymatically produced in mammals and H₂S-producing enzymes are expressed throughout the vascular wall. We previously reported that H₂S-induced vasodilation is mediated through transient receptor potential cation channel subfamily V member 4 (TRPV4) and large conductance (BK_Ca) potassium channels; however, regulators of this pathway have not been defined. Previous reports have shown that membrane cholesterol limits activity of TRPV4 and BK_Ca potassium channels. The current study examined the ability of endothelial cell (EC) plasma membrane (PM) cholesterol to regulate H₂S-induced vasodilation. We hypothesized that EC PM cholesterol hinders H₂S-mediated vasodilation in large mesenteric arteries. In pressurized, U46619 pre-constricted mesenteric arteries, decreasing EC PM cholesterol in large arteries using methyl-β-cyclodextrin (MBCD, 100 µM) increased H₂S-induced dilation (NaHS 10, 100 µM) but MBCD treatment had no effect in small arteries. Enface fluorescence showed EC PM cholesterol content is higher in large mesenteric arteries than in smaller arteries. The NaHS-induced vasodilation following MBCD treatment in large arteries was blocked by TRPV4 and BK_Ca channel inhibitors (GSK219384A, 300 nM and iberiotoxin, 100 nM, respectively). Immunohistochemistry of mesenteric artery cross-sections show that TRPV4 and BK_Ca are both present in EC of large and small arteries. Cholesterol supplementation into EC PM of small arteries abolished NaHS-induced vasodilation but the cholesterol enantiomer, epicholesterol, had no effect. Proximity ligation assay studies did not show a correlation between EC PM cholesterol content and the association of TRPV4 and BK. Collectively, these results demonstrate that EC PM cholesterol limits H₂S-induced vasodilation through effects on EC TRPV4 and BK_Ca channels. Full article

The RhoA-ROCK signaling pathway is associated with the protective effects of hydrogen sulfide (H₂S) against cerebral ischemia. H₂S protects rat hippocampal neurons (RHNs) against hypoxia-reoxygenation (H/R) injury by promoting phosphorylation of RhoA at Ser188. However, effect of H₂S on the phosphorylation of ROCK₂-related sites is unclear. The present study was designed to investigate whether H₂S can play a role in the phosphorylation of ROCK₂ at Tyr722, and explore whether this role mediates the protective effect of H/R injury in RHNs. Prokaryotic recombinant plasmids ROCK₂^wild-pGEX-6P-1 and ROCK₂^Y722F-pGEX-6P-1 were constructed and transfected into E. coli in vitro, and the expressed protein, GST-ROCK₂^wild and GST-ROCK₂^Y722F were used for phosphorylation assay in vitro. Eukaryotic recombinant plasmids ROCK₂^Y722-pEGFP-N1 and ROCK₂^Y722F-pEGFP-N1 as well as empty plasmid were transfected into the RHNs. Western blot assay and whole-cell patch-clamp technique were used to detect phosphorylation of ROCK₂ at Tyr722 and BK_Ca channel current in the RHNs, respectively. Cell viability, leakages of intracellular enzymes lactate dehydrogenase (LDH), and nerve-specific enolase (NSE) were measured. The H/R injury was indicated by decrease of cell viability and leakages of intracellular LDH and NSE. The results of Western blot have shown that NaHS, a H₂S donor, significantly promoted phosphorylation of GST-ROCK₂^wild at Tyr722, while no phosphorylation of GST-ROCK₂^Y722F was detected. The phosphorylation of ROCK₂^wild promoted by NaHS was also observed in RHNs. NaHS induced more potent effects on protection against H/R injury, phosphorylation of ROCK₂ at Tyr722, inhibition of ROCK₂ activity, as well as increase of the BK_Ca current in the ROCK₂^Y722-pEGFP-N1-transfected RHNs. Our results revealed that H₂S protects the RHNs from H/R injury through promoting phosphorylation of ROCK₂ at Tyr722 to inhibit ROCK₂ activity and potentially by opening channel currents. Full article

QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of K_V7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K⁺ current (I_K(M)), Ca²⁺-activated K⁺ current (I_K(Ca)), large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, and erg-mediated K⁺ current (I_K(erg)) identified from pituitary tumor (GH₃) cells. Addition of QO-58 can increase the amplitude of I_K(M) and I_K(Ca) in a concentration-dependent fashion, with effective EC₅₀ of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of I_K(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (V_hys) of I_K(M) evoked by upright triangular ramp pulse (V_ramp) was enhanced by adding QO-58. The probabilities of M-type K⁺ (K_M) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH₃-cell exposure to QO-58 effectively increased the amplitude of I_K(Ca) as well as enhanced the activity of BK_Ca channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BK_Ca-channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BK_Ca channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of I_K(erg) amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or K_Ca1.1 channel. Overall, dual activation of I_K(M) and I_K(Ca) caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/K_V7 selective. Full article

Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca²⁺-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca²⁺-regulated potassium (mitoBK_Ca) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BK_Ca channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BK_Ca channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBK_Ca channel in a bronchial epithelial cell line were described. Full article

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one) is a novel and selective activator of KCNQ2/KCNQ3 K⁺ channels. However, it remains largely unknown whether this compound can modify any other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH₃ lactotrophs were investigated in this study. QO-40 stimulated Ca²⁺-activated K⁺ current (I_K(Ca)) with an EC₅₀ value of 2.3 μM in these cells. QO-40-stimulated I_K(Ca) was attenuated by the further addition of GAL-021 or paxilline but not by linopirdine or TRAM-34. In inside-out mode, this compound added to the intracellular leaflet of the detached patches stimulated large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BK_Ca channels. The K_D value required for the QO-40-mediated decrease in the slow component at the mean closure time was 1.96 μM. This compound shifted the steady-state activation curve of BK_Ca channels to a less positive voltage and decreased the gating charge of the channel. The application of QO-40 also increased the hysteretic strength of BK_Ca channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing α-hSlo, QO-40 stimulated BK_Ca channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BK_Ca channel to increase the amplitude of I_K(Ca) in GH₃ cells. Full article

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BK_Ca current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BK_Ca currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BK_Ca. Real-time PCR was used to measure BK_Ca mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BK_Ca currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BK_Ca channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BK_Ca-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BK_Ca mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BK_Ca current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain. Full article

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca²⁺-activated K⁺ channel (BK_Ca) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca²⁺ imaging, and computational modeling, we evaluated the effects of S1P on the Ca²⁺-activated K⁺ currents (I_K(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BK_Ca channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca²⁺ concentration (Ca_i) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BK_Ca was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed I_K(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of I_K(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced I_K(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BK_Ca conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited I_K(Ca) and the permissive role of S1P on the BK_Ca activity was also effectively observed in the PC12 cell system. The S1P-mediated I_K(Ca) stimulation may result from the elevated Ca_i, whereas the inhibition of BK_Ca activity by S1P appears to be direct. By the differentiated tailoring BK_Ca channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells. Full article

Opening of large conductance calcium-activated and voltage-dependent potassium (BK_Ca) channels hyperpolarizes plasma membranes of smooth muscle (SM) to cause vasodilation, underling a key mechanism for mediating uterine artery (UA) dilation in pregnancy. Hydrogen sulfide (H₂S) has been recently identified as a new UA vasodilator, yet the mechanism underlying H₂S-induced UA dilation is unknown. Here, we tested whether H₂S activated BK_Ca channels in human UA smooth muscle cells (hUASMC) to mediate UA relaxation. Multiple BK_Ca subunits were found in human UA in vitro and hUASMC in vitro, and high β1 and γ1 proteins were localized in SM cells in human UA. Baseline outward currents, recorded by whole-cell and single-channel patch clamps, were significantly inhibited by specific BK_Ca blockers iberiotoxin (IBTX) or tetraethylammonium, showing specific BK_Ca activity in hUASMC. H₂S dose (NaHS, 1–1000 µM)-dependently potentiated BK_Ca currents and open probability. Co-incubation with a Ca²⁺ blocker nifedipine (5 µM) or a chelator (ethylene glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM) did not alter H₂S-potentiated BK_Ca currents and open probability. NaHS also dose-dependently relaxed phenylephrine pre-constricted freshly prepared human UA rings, which was inhibited by IBTX. Thus, H₂S stimulated human UA relaxation at least partially via activating SM BK_Ca channels independent of extracellular Ca²⁺. Full article

GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca²⁺-activated K⁺ (BK_Ca) channels has been reported. In pituitary tumor (GH₃) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca²⁺-activated K⁺ current (I_K(Ca)) in a concentration-dependent manner with an effective IC₅₀ of 2.33 μM. GAL-021-mediated reduction of I_K(Ca) was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BK_Ca channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BK_Ca channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BK_Ca channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K⁺ current with an effective IC₅₀ of 3.75 μM; however, its presence did not alter the amplitude of erg-mediated K⁺ current, or mildly suppressed delayed-rectifier K⁺ current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing α-hSlo, the addition of GAL-021 was also able to suppress the BK_Ca-channel open probabilities, and GAL-021-mediated suppression of BK_Ca-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BK_Ca channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo. Full article